Drug delivery compositions and medical devices containing block copolymer

ABSTRACT

A composition for delivery of a therapeutic agent is provided. The composition comprises: (a) a biocompatible block copolymer comprising one or more elastomeric blocks and one or more thermoplastic blocks and (b) a therapeutic agent, wherein the block copolymer is loaded with the therapeutic agent. The block copolymer is preferably of the formula X-(AB) n, where A is an elastomeric block, B is a thermoplastic block, n is a positive whole number and X is a seed molecule. The elastomeric blocks are preferably polyolefin blocks, and the thermoplastic blocks are preferably selected from vinyl aromatic blocks and methacrylate blocks. According to another aspect of the invention, a medical device is provided, at least a portion of which is insertable or implantable into the body of a patient. The medical device comprises (a) the above biocompatible block copolymer and (b) a therapeutic agent, wherein the block copolymer is loaded with the therapeutic agent. According to another aspect of the present invention, a method of treatment is provided in which the above device is implanted or inserted into a patient, resulting in the release of therapeutic agent in the patient over an extended period. According to yet another aspect of the invention, a coated medical device is provided which comprises: (a) an intravascular or intervascular medical device and (b) a coating over at least a portion of the intravascular or intervascular a medical device, wherein the coating comprises the above biocompatible block copolymer.

FIELD OF THE INVENTION

[0001] The present invention relates to compositions for therapeuticagent delivery comprising a therapeutic-agent-loaded block copolymer.The present invention also relates to biocompatible block copolymermaterials for use in connection with intravascular or intervascularmedical devices.

BACKGROUND AND SUMMARY OF THE INVENTION

[0002] Polymers that release drug upon implantation or insertion intothe body are known. However, a need remains in the art for a polymerthat is effective for drug-release, while at the same time having goodmechanical integrity and biocompatibility.

[0003] It is also known to use polymers in connection with implantableor insertable medical devices. However, such polymers frequently elicita vigorous immune or foreign body response. This is particularly true ofintravascular or intervascular medical devices, which commonly sufferfrom the consequences of inflammation and neointimal thickening afterplacement within the vasculature.

[0004] The above and other needs in the prior art have been met by thepresent invention. According to one aspect of the invention, acomposition for delivery of a therapeutic agent is provided, whichcomprises: (a) a biocompatible block copolymer comprising one or moreelastomeric blocks and one or more thermoplastic blocks and (b) atherapeutic agent, wherein the block copolymer is loaded with thetherapeutic agent.

[0005] Numerous therapeutic agents are appropriate for use in connectionwith the present invention including anti-thrombotic agents,anti-proliferative agents, anti-inflammatory agents, anti-migratoryagents, agents affecting extracellular matrix production andorganization, antineoplastic agents, anti-mitotic agents, anestheticagents, anti-coagulants, vascular cell growth promoters, vascular cellgrowth inhibitors, cholesterol-lowering agents, vasodilating agents,agents that interfere with endogenous vascoactive mechanisms, andcombinations thereof. One specific example of a therapeutic agent ispaclitaxel. The loaded block copolymer preferably comprises 0.1 to 70 wt% therapeutic agent.

[0006] Regarding the polymer configuration, the block copolymer ispreferably of the formula X-(AB)_(n), where A is an elastomeric block, Bis a thermoplastic block, n is a positive whole number and X is a seedmolecule.

[0007] Regarding the blocks within the copolymer, the elastomeric blocksare preferably polyolefin blocks. More preferably, the polyolefin blocksare of the general formula —(CRR′-CH₂)_(n)—, where R and R′ are linearor branched aliphatic groups or cyclic aliphatic groups. Even morepreferably, the polyolefin blocks are polyisobutylene blocks. The amountof polyolefin blocks preferably ranges from between 95 and 45 mol % ofthe block copolymer.

[0008] The thermoplastic blocks are preferably selected from vinylaromatic blocks and methacrylate blocks. The methacrylate blocks arepreferably selected from methylmethacrylate, ethylmethacrylate andhydroxyethyl methacrylate monomers, as well as blocks of mixtures ofthese monomers. The vinyl aromatic polymer blocks are preferablyselected from blocks of styrene and α-methylstyrene, as well as blocksof mixtures of these monomers.

[0009] The molecular weight of the block copolymer preferably rangesfrom 80,000 to 300,000 Daltons. In some embodiments, the molecularweight of the polyolefin blocks preferably ranges from 60,000 to 200,000Daltons, and the molecular weight of the vinyl aromatic polymer blockspreferably ranges from 20,000 to 100,000 Daltons.

[0010] According to another aspect of the present invention, a medicaldevice is provided, at least a portion of which is insertable orimplantable into the body of a patient. The medical device comprises (a)the above block copolymer and (b) a therapeutic agent, wherein the blockcopolymer is loaded with the therapeutic agent.

[0011] In some embodiments, only a portion of the medical devicecomprises the block copolymer. As an example, the portion of the medicaldevice can be in the form of a coating on the medical device. Preferredcoating dimensions are 0.1 to 50 microns in thickness.

[0012] Preferably, the therapeutic agent is released over an extendedperiod after implantation in a patient.

[0013] Preferred sites for implantation or insertion of the medicaldevice are the coronary vasculature, peripheral vasculature, esophagus,trachea, colon, gastrointestinal tract, biliary tract, urinary tract,prostate and brain.

[0014] In some embodiments, the medical device is adapted such that atleast a portion of the block copolymer is exposed to bodily fluid uponinsertion or implantation in the body. In others, the medical device isadapted to expose at least a portion of the block copolymer to tissuesuch as solid tissue.

[0015] Preferred medical devices include catheters, guide wires,balloons, filters, stents, stent grafts, vascular grafts, vascularpatches, shunts and intraluminal paving systems. In some embodiments,the medical device is provided with a sheath for covering the blockcopolymer during insertion into the body to prevent prematuretherapeutic agent release.

[0016] In certain embodiments, the medical device further comprises apolymer or copolymer of one or more of the following: a polycarboxylicacid, a cellulose acetate polymer, a cellulose nitrate polymer, agelatin, a polyvinylpyrrolidone, a cross-linked polyvinylpyrrolidone, apolyanhydride, a polyamide, a polyvinyl alcohol, a polyvinyl ether, apolyvinyl aromatic, a polyethylene oxide, a glycosaminoglycan, apolysaccharide, a polyester, a polyacrylamide, a polyether, a polyethersulfone, a polycarbonate, a polyalkylene, a halogenated polyalkylene, apolyurethane, a polyorthoester, a polypeptide, a silicone, a siloxanepolymer, a polylactic acid, a polyglycolic acid, a polycaprolactone, apolyhydroxybutyrate valerate, a fibrin, a collagen, a collagenderivative or a hyaluronic acid. Particularly preferred polymers andcopolymers are polyacrylic acids, ethylene-vinyl acetate copolymers, andcopolymers of polylactic acid and polycaprolactone.

[0017] Such polymers or copolymers can be blended with the biocompatibleblock copolymer, or they can be provided in a layer that does notcontain the biocompatible block copolymer.

[0018] According to another aspect of the present invention, a method oftreatment is provided in which the above device is implanted or insertedinto a patient, resulting in the release of therapeutic agent in thepatient over an extended period of time.

[0019] According to yet another aspect of the invention, a coatedmedical device is provided which comprises: (a) an intravascular orintervascular medical device; and (b) a coating over at least a portionof the intravascular or intervascular medical device, the coatingcomprising the above biocompatible block copolymer. Preferredintravascular or intervascular medical devices for this aspect of theinvention include balloons, stents, stent grafts, vascular grafts,vascular patches, shunts, catheters and filters.

[0020] One advantage of the present invention is that it provides apolymer-based drug delivery composition with good mechanical integrity.

[0021] Another advantage is that a polymer-based drug deliverycomposition can be provided that has good biocompatibility.

[0022] Another advantage of the present invention is that medicaldevices can be provided that, upon placement in the vasculature, resultin reduced inflammation and neointimal thickening relative to othertraditionally used polymeric materials.

[0023] Still other embodiments and advantages will become readilyapparent to those skilled in the art upon review of the Specificationand claims to follow.

BRIEF DESCRIPTION OF THE DRAWINGS

[0024]FIG. 1 illustrates release rate as a function of time for stentscoated with polystyrene-polyisobutylene-polystyrene copolymer andpaclitaxel in varying ratios.

[0025] FIGS. 2A-2D are photographs, after 28 days in a porcine coronaryartery, of (1) a bare stainless steel stent, (2) a stainless steel stentwith a coating of traditional “biostable” polyurethane polymer, (3) astainless steel stent with a coating of a traditional “biodegradable”copolymer of polylactic acid (“PLA”) and polyglycolic acid (“PGA”) and(4) a stainless steel stent covered with a coating ofpolystyrene-polyisobutylene-polystyrene copolymer in accordance with anembodiment of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

[0026] The present invention relates to compositions comprising atherapeutic-agent-loaded block copolymer that are useful for delivery ofa therapeutic agent and to biocompatible block copolymer materialsuseful, for example, in connection with intravascular or intervascularmedical devices.

[0027] Block copolymers suitable for the practice of the presentinvention preferably have a first elastomeric block and a secondthermoplastic block. More preferably, the block copolymers have acentral elastomeric block and thermoplastic end blocks. Even morepreferably, such block copolymers have the general structure:

[0028] (a) BAB or ABA (linear triblock),

[0029] (b) B(AB)_(n) or A(BA)_(n) (linear alternating block), or

[0030] (c) X-(AB)_(n) or X-(BA)_(n) (includes diblock, triblock andother radial block copolymers),

[0031] where A is an elastomeric block, B is a thermoplastic block, n isa positive whole number and X is a starting seed molecule.

[0032] Most preferred are X-(AB)_(n) structures, which are frequentlyreferred to as diblock copolymers and triblock copolymers where n=1 andn=2, respectively (this terminology disregards the presence of thestarting seed molecule, for example, treating A-X-A as a single A blockwith the triblock therefore denoted as BAB). Where n=3 or more, thesestructures are commonly referred to as star-shaped block copolymers.

[0033] The A blocks are preferably soft elastomeric components which arebased upon one or more polyolefins, more preferably a polyolefinic blockhaving alternating quaternary and secondary carbons of the generalformulation: —(CRR′—CH₂)_(n)—, where R and R′ are linear or branchedaliphatic groups such as methyl, ethyl, propyl, isopropyl, butyl,isobutyl and so forth, or cyclic aliphatic groups such as cyclohexane,cyclopentane, and the like, with and without pendant groups.

[0034] Polymers of isobutylene,

[0035] (i.e., polymers where R and R′ are the same and are methylgroups) are most preferred.

[0036] The B blocks are preferably hard thermoplastic blocks that, whencombined with the soft A blocks, are capable of, inter alia, altering oradjusting the hardness of the resulting copolymer to achieve a desiredcombination of qualities. Preferred B blocks are polymers ofmethacrylates or polymers of vinyl aromatics. More preferred B blocksare (a) made from monomers of styrene

[0037] styrene derivatives (e.g., α-methylstyrene, ring-alkylatedstyrenes or ring-halogenated styrenes) or mixtures of the same or are(b) made from monomers of methylmethacrylate, ethylmethacrylatehydroxyethyl methacrylate or mixtures of the same.

[0038] The properties of the block copolymers used in connection withthe present invention will depend upon the lengths of the A blocks and Bblocks, as well as the relative amounts of each.

[0039] For example, the elastomeric properties of the block copolymerwill depend on the length of the A block chains, with a weight averagemolecular weight of from about 2,000 to about 30,000 Daltons tending toproduce rather inelastic products, and a weight average molecular weightof 40,000 Daltons or above tending to produce products that are moresoft and rubbery. Hence, for purposes of the present invention, thecombined molecular weight of the block copolymer is preferably in excessof 40,000 Daltons, more preferably in excess of 60,000 Daltons, and mostpreferably between about 90,000 to about 300,000 Daltons.

[0040] As another example, the hardness of the block copolymer isproportional to the relative amount of B blocks. In general, thecopolymer has a preferred hardness that is between about Shore 20A andShore 75D, and more preferably between about Shore 40A and Shore 90A.This result can be achieved by varying the proportions of the A and Bblocks, with a lower relative proportion of B blocks resulting in acopolymer of lower hardness, and a higher relative proportion of Bblocks resulting in a copolymer of higher hardness. As a specificexample, high molecular weight (i.e., greater than 100,000 Daltons)polyisobutylene is a soft gummy material with a Shore hardness ofapproximately 10A. Polystyrene, is much harder, typically having a Shorehardness on the order of 100D. As a result, when blocks ofpolyisobutylene and styrene are combined, the resulting copolymer canhave a range of hardnesses from as soft as Shore 10A to as hard as Shore100D, depending upon the relative amounts of polystyrene andpolyisobutylene. In general, to achieve a preferred hardness rangingfrom Shore 30A to Shore 90A, the amount of polystyrene ranges frombetween 2 and 25 mol %. More preferably, the preferred hardness rangesfrom Shore 35A to Shore 70A and the amount of polystyrene ranges from 5to 20 mol %.

[0041] Polydispersity (i.e., the ratio of weight average molecularweight to number average molecular weight) gives an indication of themolecular weight distribution of the copolymer, with valuessignificantly greater than 4 indicating a broad molecular weightdistribution. The polydispersity has a value of one when all moleculeswithin a sample are the same size. Typically, the copolymers for use inconnection with the present invention have a relatively tight molecularweight distribution, with a polydispersity of about 1.1 to 1.7.

[0042] One advantage associated with the above-described copolymers istheir high tensile strength. For example, the tensile strength oftriblock copolymers of polystyrene-polyisobutylene-polystyrenefrequently ranges from 2,000 to 4,000 psi or more.

[0043] Another advantage of such copolymers is their resistance tocracking and other forms of degradation under in vivo conditions. Inaddition, these polymers exhibit excellent biocompatibility, includingvascular compatibility, as demonstrated by their tendency to provokeminimal adverse tissue reactions as demonstrated by reducedpolymorphonuclear leukocyte and reduced macrophage activity. Stillfurther, these polymers are generally hemocompatible as demonstrated bytheir ability to minimize thrombotic occlusion of small vessels asdemonstrated by coating such copolymers on coronary stents. See Example6 below.

[0044] The above-described block copolymers can be made using anyappropriate method known in the art. A preferred process of making theblock copolymers is by carbocationic polymerization involving an initialpolymerization of a monomer or mixtures of monomers to form the Ablocks, followed by the subsequent addition of a monomer or a mixture ofmonomers capable of forming the B blocks.

[0045] Such polymerization reactions can be found, for example, inAdditional U.S. Pat. Nos. 4,276,394, 4,316,973, 4,342,849, 4,910,321,4,929,683, 4,946,899, 5,066,730, 5,122,572 and/or Re. 34,640. Each ofthese patents is hereby incorporated by reference in its entirety.

[0046] The techniques disclosed in these patents generally involve a“catalyst starting molecule” (also referred to as “initiators”,“telechelic starting molecules”, “seed molecules” or “inifers”), whichcan be used to create X-(AB)_(n) structures, where X is the catalyststarting molecule, and n can be 1, 2, 3 or more. As noted above, theresulting molecules are referred to as diblock copolymers where n is 1,triblock copolymers (disregarding the presence of the starting molecule)where n is 2, and star-shaped block copolymers where n is 3 or more.

[0047] In general, the polymerization reaction is conducted underconditions that minimize or avoid chain transfer and termination of thegrowing polymer chains. Steps are taken to keep active hydrogen atoms(water, alcohol and the like) to a minimum. The temperature for thepolymerization is usually between −10° and −90° C., the preferred rangebeing between −60° and −80° C., although lower temperatures may beemployed if desired.

[0048] Preferably, one or more A blocks, for example, polyisobutyleneblocks, are formed in a first step, followed by the addition of Bblocks, for example, polystyrene blocks, at the ends of the A blocks.

[0049] More particularly, the first polymerization step is generallycarried out in an appropriate solvent system, typically a mixture ofpolar and non-polar solvents such as methyl chloride and hexanes. Thereaction bath typically contains:

[0050] the aforementioned solvent system,

[0051] olefin monomer, such as isobutylene,

[0052] an initiator (inifer or seed molecule) such as tert-ester,tert-ether, tert-hydroxyl or tert-halogen containing compounds, and moretypically cumyl esters of hydrocarbon acids, alkyl cumyl ethers, cumylhalides and cumyl hydroxyl compounds as well as hindered versions of theabove,

[0053] a coinitiator, typically a Lewis Acid, such as boron trichlorideor titanium tetrachloride.

[0054] Electron pair donors such as dimethyl acetamide, dimethylsulfoxide, or dimethyl phthalate can be added to the solvent system.Additionally, proton-scavengers that scavenge water, such as2,6-di-tert-butylpyridine, 4-methyl-2,6-di-tert-butylpyridine,1,8-bis(dimethylamino)-naphthalene, or diisopropylethyl amine can beadded.

[0055] The reaction is commenced by removing the tert-ester, tert-ether,tert-hydroxyl or tert-halogen (herein called the “tert-leaving groups”)from the seed molecule by reacting it with the Lewis acid. In place ofthe tert-leaving groups is a quasi-stable or “living” cation which isstabilized by the surrounding tertiary carbons as well as the polarsolvent system and electron pair donors. After obtaining the cation, theA block monomer, such as isobutylene, is introduced which cationicallypropagates or polymerizes from each cation on the seed molecule. Whenthe A block is polymerized, the propagated cations remain on the ends ofthe A blocks. The B block monomer, such as styrene, is then introducedwhich polymerizes and propagates from the ends of the A block. Once theB blocks are polymerized, the reaction is terminated by adding atermination molecule such as methanol, water and the like.

[0056] As is normally the case, product molecular weights are determinedby reaction time, reaction temperature, the nature and concentration ofthe reactants, and so forth. Consequently, different reaction conditionswill produce different products. In general, synthesis of the desiredreaction product is achieved by an iterative process in which the courseof the reaction is monitored by the examination of samples takenperiodically during the reaction—a technique widely employed in the art.To achieve the desired product, an additional reaction may be requiredin which reaction time and temperature, reactant concentration, and soforth are changed.

[0057] Additional details regarding cationic processes for makingcopolymers are found, for example, in U.S. Pat. Nos. 4,276,394,4,316,973, 4,342,849, 4,910,321, 4,929,683, 4,946,899, 5,066,730,5,122,572 and/or Re. 34,640.

[0058] The block copolymers described in the preceding paragraphs may berecovered from the reaction mixtures by any of the usual techniquesincluding evaporation of solvent, precipitation with a non-solvent suchas an alcohol or alcohol/acetone mixture, followed by drying, and soforth. In addition, purification of the copolymer can be performed bysequential extraction in aqueous media, both with and without thepresence of various alcohols, ethers and ketones.

[0059] Once synthesized, the block copolymers can be used, for example,to provide therapeutic-agent-loaded block copolymer compositions fortherapeutic agent delivery, or to provide biocompatible intravascular orintervascular devices.

[0060] For a given mode of administration, a wide variety of therapeuticagents, including genetic therapeutic agents, non-genetic therapeuticagents, and cells, can be used in conjunction with the block copolymersof the invention.

[0061] Exemplary non-genetic therapeutic agents include:

[0062] anti-thrombotic agents such as heparin, heparin derivatives,urokinase, and PPack (dextrophenylalanine proline argininechloromethylketone);

[0063] anti-inflammatory agents such as dexamethasone, prednisolone,corticosterone, budesonide, estrogen, sulfasalazine and mesalamine;

[0064] antineoplastic/antiproliferative/anti-miotic agents such aspaclitaxel, 5-fluorouracil, cisplatin, vinblastine, vincristine,epothilones, endostatin, angiostatin, angiopeptin, monoclonal antibodiescapable of blocking smooth muscle cell proliferation, and thymidinekinase inhibitors;

[0065] anesthetic agents such as lidocaine, bupivacaine and ropivacaine;

[0066] anti-coagulants such as D-Phe-Pro-Arg chloromethyl ketone, an RGDpeptide-containing compound, heparin, hirudin, antithrombin compounds,platelet receptor antagonists, anti-thrombin antibodies, anti-plateletreceptor antibodies, aspirin, prostaglandin inhibitors, plateletinhibitors and tick antiplatelet peptides;

[0067] vascular cell growth promoters such as growth factors,transcriptional activators, and translational promotors;

[0068] vascular cell growth inhibitors such as growth factor inhibitors,growth factor receptor antagonists, transcriptional repressors,translational repressors, replication inhibitors, inhibitory antibodies,antibodies directed against growth factors, bifunctional moleculesconsisting of a growth factor and a cytotoxin, bifunctional moleculesconsisting of an antibody and a cytotoxin;

[0069] protein kinase and tyrosine kinase inhibitors (e.g., tyrphostins,genistein, quinoxalines);

[0070] prostacyclin analogs;

[0071] cholesterol-lowering agents;

[0072] angiopoietins;

[0073] antimicrobial agents such as triclosan, cephalosporins,aminoglycosides and nitrofurantoin;

[0074] cytotoxic agents, cytostatic agents and cell proliferationaffectors;

[0075] vasodilating agents; and

[0076] agents that interfere with endogenous vascoactive mechanisms.

[0077] Exemplary genetic therapeutic agents include:

[0078] anti-sense DNA and RNA;

[0079] DNA coding for:

[0080] anti-sense RNA,

[0081] tRNA or rRNA to replace defective or deficient endogenousmolecules,

[0082] angiogenic factors including growth factors such as acidic andbasic fibroblast growth factors, vascular endothelial growth factor,epidermal growth factor, transforming growth factor α and β,platelet-derived endothelial growth factor, platelet-derived growthfactor, tumor necrosis factor a, hepatocyte growth factor and insulinlike growth factor,

[0083] cell cycle inhibitors including CD inhibitors,

[0084] thymidine kinase (“TK”) and other agents useful for interferingwith cell proliferation, and

[0085] the family of bone morphogenic proteins (“BMP's”), includingBMP-2, BMP-3, BMP-4, BMP-5, BMP-6 (Vgr-1), BMP-7 (OP-1), BMP-8, BMP-9,BMP-10, BMP-11, BMP-12, BMP-13, BMP-14, BMP-15, and BMP-16. Currentlypreferred BMP's are any of BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 and BMP-7.

[0086] These dimeric proteins can be provided as homodimers,heterodimers, or combinations thereof, alone or together with othermolecules. Alternatively or, in addition, molecules capable of inducingan upstream or downstream effect of a BMP can be provided. Suchmolecules include any of the “hedgehog” proteins, or the DNA's encodingthem.

[0087] Vectors of interest for delivery of genetic therapeutic agentsinclude

[0088] Plasmids

[0089] Viral vectors such as adenovirus (AV), adenoassociated virus(AAV) and lentivirus

[0090] Non-viral vectors such as lipids, liposomes and cationic lipids.

[0091] Cells include cells of human origin (autologous or allogeneic),including stem cells, or from an animal source (xenogeneic), which canbe genetically engineered if desired to deliver proteins of interest.

[0092] Several of the above and numerous additional therapeutic agentsappropriate for the practice of the present invention are disclosed inU.S. Pat. No. 5,733,925 assigned to NeoRx Corporation, the entiredisclosure of which is incorporated by reference. Therapeutic agentsdisclosed in this patent include the following:

[0093] “Cytostatic agents” (i.e., agents that prevent or delay celldivision in proliferating cells, for example, by inhibiting replicationof DNA or by inhibiting spindle fiber formation). Representativeexamples of cytostatic agents include modified toxins, methotrexate,adriamycin, radionuclides (e.g., such as disclosed in Fritzberg et al.,U.S. Pat. No. 4,897,255), protein kinase inhibitors, includingstaurosporin, a protein kinase C inhibitor of the following

[0094] formula, as well as diindoloalkaloids having one of the followinggeneral structures:

[0095] as well as stimulators of the production or activation ofTGF-beta, including tamoxifen and derivatives of functional equivalents(e.g., plasmin, heparin, compounds capable of reducing the level orinactivating the lipoprotein Lp(a) or the glycoproteinapolipoprotein(a)) thereof, TGF-beta or functional equivalents,derivatives or analogs thereof, suramin, nitric oxide releasingcompounds (e.g., nitroglycerin) or analogs or functional equivalentsthereof, paclitaxel or analogs thereof (e.g., taxotere), inhibitors ofspecific enzymes (such as the nuclear enzyme DNA topoisomerase II andDNA polymerase, RNA polymerase, adenyl guanyl cyclase), superoxidedismutase inhibitors, terminal deoxynucleotidyl-transferase, reversetranscriptase, antisense oligonucleotides that suppress smooth musclecell proliferation and the like.

[0096] Other examples of “cytostatic agents” include peptidic or mimeticinhibitors (i.e., antagonists, agonists, or competitive ornon-competitive inhibitors) of cellular factors that may (e.g., in thepresence of extracellular matrix) trigger proliferation of smooth musclecells or pericytes: e.g., cytokines (e.g., interleukins such as IL-1),growth factors (e.g., PDGF, TGF-alpha or -beta, tumor necrosis factor,smooth muscle- and endothelial-derived growth factors, i.e., endothelin,FGF), homing receptors (e.g., for platelets or leukocytes), andextracellular matrix receptors (e.g., integrins). Representativeexamples of useful therapeutic agents in this category of cytostaticagents addressing smooth muscle proliferation include: subfragments ofheparin, triazolopyrimidine (trapidil; a PDGF antagonist), lovastatin,and prostaglandins E1 or I2.

[0097] Agents that inhibit migration of vascular smooth muscle cellsfrom the medial wall into the intima (“anti-migratory agents”). Severalpreferred examples are derived from phenylalanine (cytochalasins),tryptophan (chaetoglobosins), or leucine (aspochalasins), resulting in abenzyl, indol-3-yl methyl or isobutyl group, respectively, at positionC-3 of a substituted perhydroisoindole-1-one moiety (Formula V or VI).

[0098] The perhydroisoindole moiety in turn contains an 11-, 13- or14-atom carbocyclic- or oxygen-containing ring linked to positions C-8and C-9. All naturally occurring cytochalasins contain a methyl group atC-5; a methyl or methylene group at C-12; and a methyl group at C-14 orC-16. Exemplary molecules include cytochalasin A, cytochalasin B,cytochalasin C, cytochalasin D, cytochalasin E, cytochalasin F,cytochalasin G, cytochalasin H, cytochalasin J, cytochalasin K,cytochalasin L, cytochalasin M, cytochalasin N, cytochalasin O,cytochalasin P, cytochalasin Q, cytochalasin R, cytochalasin S,chaetoglobosin A, chaetoglobosin B, chaetoglobosin C, chaetoglobosin D,chaetoglobosin E, chaetoglobosin F, chaetoglobosin J, chaetoglobosin K,deoxaphomin, proxiphomin, protophomin, zygosporin D, zygosporin E,zygosporin F, zygosporin G, aspochalasin B, aspochalasin C, aspochalasinD and the like, as well as functional equivalents and derivativesthereof. Certain cytochalasin derivatives are set forth in JapanesePatent Nos. 72 01,925; 72 14,219; 72 08,533; 72 23,394; 72 01924; and 7204,164.

[0099] Other representative examples of anti-migratory agents includeinhibitors (i.e., agonists and antagonists, and competitive ornon-competitive inhibitors) of chemotactic factors and their receptors(e.g., complement chemotaxins such as C5a, C5a desarg or C4a;extracellular matrix factors, e.g., collagen degradation fragments), orof intracellular cytoskeletal proteins involved in locomotion (e.g.,actin, cytoskeletal elements, and phosphatases and kinases involved inlocomotion). Representative examples of useful therapeutic agents inthis category of anti-migratory agents include: caffeic acid derivativesand nilvadipine (a calcium antagonist), and steroid hormones.

[0100] Agents that inhibit the intracellular increase in cell volume(i.e., the tissue volume occupied by a cell) such as cytoskeletalinhibitors or metabolic inhibitors. Representative examples ofcytoskeletal inhibitors include colchicine, vinblastin, cytochalasins,paclitaxel and the like, which act on microtubule and microfilamentnetworks within a cell. Representative examples of metabolic inhibitorsinclude staurosporin, trichothecenes, and modified diphtheria and ricintoxins, Pseudomonas exotoxin and the like. Trichothecenes include simpletrichothecenes (i.e., those that have only a central sesquiterpenoidstructure) and macrocyclic trichothecenes (i.e., those that have anadditional macrocyclic ring), e.g., a verrucarins or roridins, includingVerrucarin A, Verrucarin B, Verrucarin J (Satratoxin C), Roridin A,Roridin C, Roridin D, Roridin E (Satratoxin D), Roridin H.

[0101] Agents acting as an inhibitor that blocks cellular proteinsynthesis and/or secretion or organization of extracellular matrix(i.e., an “anti-matrix agent”). Representative examples of “anti-matrixagents” include inhibitors (i.e., agonists and antagonists andcompetitive and non-competitive inhibitors) of matrix synthesis,secretion and assembly, organizational cross-linking (e.g.,transglutaminases cross-linking collagen), and matrix remodeling (e.g.,following wound healing). A representative example of a usefultherapeutic agent in this category of anti-matrix agents is colchicine,an inhibitor of secretion of extracellular matrix. Another example istamoxifen for which evidence exists regarding its capability to organizeand/or stabilize as well as diminish smooth muscle cell proliferationfollowing angioplasty. The organization or stabilization may stem fromthe blockage of vascular smooth muscle cell maturation in to apathologically proliferating form.

[0102] Agents that are cytotoxic to cells, particularly cancer cells.Preferred agents are Roridin A, Pseudomonas exotoxin and the like oranalogs or functional equivalents thereof. A plethora of suchtherapeutic agents, including radioisotopes and the like, have beenidentified and are known in the art. In addition, protocols for theidentification of cytotoxic moieties are known and employed routinely inthe art.

[0103] A number of the above therapeutic agents and several others havealso been identified as candidates for vascular treatment regimens, forexample, as agents targeting restenosis. Such agents are appropriate forthe practice of the present invention and include one or more of thefollowing:

[0104] Ca-channel blockers including:

[0105] Benzothiazapines such as diltiazem and clentiazem

[0106] Dihydropyridines such as nifedipine, amlodipine and nicardapine

[0107] Phenylalkylamines such as verapamil

[0108] Serotonin pathway modulators including:

[0109] 5-HT antagonists such as ketanserin and naftidrofuryl

[0110] 5-HT uptake inhibitors such as fluoxetine

[0111] Cyclic nucleotide pathway agents including:

[0112] Phosphodiesterase inhibitors such as cilostazole and dipyridamole

[0113] Adenylate/Guanylate cyclase stimulants such as forskolin

[0114] Adenosine analogs

[0115] Catecholamine modulators including:

[0116] α-antagonists such as prazosin and bunazosine

[0117] β-antagonists such as propranolol

[0118] α/β-antagonists such as labetalol and carvedilol

[0119] Endothelin receptor antagonists

[0120] Nitric oxide donors/releasing molecules including:

[0121] Organic nitrates/nitrites such as nitroglycerin, isosorbidedinitrate and amyl nitrite

[0122] Inorganic nitroso compounds such as sodium nitroprusside

[0123] Sydnonimines such as molsidomine and linsidomine

[0124] Nonoates such as diazenium diolates and NO adducts ofalkanediamines

[0125] S-nitroso compounds including low molecular weight compounds(e.g., S-nitroso derivatives of captopril, glutathione and N-acetylpenicillamine), high molecular weight compounds (e.g., S-nitrosoderivatives of proteins, peptides, oligosaccharides, polysaccharides,synthetic polymers/oligomers and natural polymers/oligomers)

[0126] C-nitroso-, O-nitroso- and N-nitroso-compounds

[0127] L-arginine

[0128] ACE inhibitors such as cilazapril, fosinopril and enalapril

[0129] ATII-receptor antagonists such as saralasin and losartin

[0130] Platelet adhesion inhibitors such as albumin and polyethyleneoxide

[0131] Platelet aggregation inhibitors including:

[0132] Aspirin and thienopyridine (ticlopidine, clopidogrel)

[0133] GP IIb/IIIa inhibitors such as abciximab, epitifibatide andtirofiban

[0134] Coagulation pathway modulators including:

[0135] Heparinoids such as heparin, low molecular weight heparin,dextran sulfate and β-cyclodextrin tetradecasulfate

[0136] Thrombin inhibitors such as hirudin, hirulog,PPACK(D-phe-L-propyl-L-arg-chloromethylketone) and argatroban

[0137] FXa inhibitors such as antistatin and TAP (tick anticoagulantpeptide)

[0138] Vitamin K inhibitors such as warfarin

[0139] Activated protein C

[0140] Cyclooxygenase pathway inhibitors such as aspirin, ibuprofen,flurbiprofen, indomethacin and sulfinpyrazone

[0141] Natural and synthetic corticosteroids such as dexamethasone,prednisolone, methprednisolone and hydrocortisone

[0142] Lipoxygenase pathway inhibitors such as nordihydroguairetic acidand caffeic acid

[0143] Leukotriene receptor antagonists

[0144] Antagonists of E- and P-selectins

[0145] Inhibitors of VCAM-1 and ICAM-1 interactions

[0146] Prostaglandins and analogs thereof including:

[0147] Prostaglandins such as PGEI and PGI2

[0148] Prostacyclin analogs such as ciprostene, epoprostenol,carbacyclin, iloprost and beraprost

[0149] Macrophage activation preventers including bisphosphonates

[0150] HMG-CoA reductase inhibitors such as lovastatin, pravastatin,fluvastatin, simvastatin and cerivastatin

[0151] Fish oils and omega-3-fatty acids

[0152] Free-radical scavengers/antioxidants such as probucol, vitamins Cand E, ebselen, trans-retinoic acid and SOD mimics

[0153] Agents affecting various growth factors including:

[0154] FGF pathway agents such as bFGF antibodies and chimeric fusionproteins

[0155] PDGF receptor antagonists such as trapidil

[0156] IGF pathway agents including somatostatin analogs such asangiopeptin and ocreotide

[0157] TGF-β pathway agents such as polyanionic agents (heparin,fucoidin), decorin, and TGF-β antibodies

[0158] EGF pathway agents such as EGF antibodies, receptor antagonistsand chimeric fusion proteins

[0159] TNF-α pathway agents such as thalidomide and analogs thereof

[0160] Thromboxane A2 (TXA2) pathway modulators such as sulotroban,vapiprost, dazoxiben and ridogrel

[0161] Protein tyrosine kinase inhibitors such as tyrphostin, genisteinand quinoxaline derivatives

[0162] MMP pathway inhibitors such as marimastat, ilomastat and metastat

[0163] Cell motility inhibitors such as cytochalasin B

[0164] Antiproliferative/antineoplastic agents including:

[0165] Antimetabolites such as purine analogs(6-mercaptopurine),pyrimidine analogs (e.g., cytarabine and 5-fluorouracil) andmethotrexate

[0166] Nitrogen mustards, alkyl sulfonates, ethylenimines, antibiotics(e.g., daunorubicin, doxorubicin), nitrosoureas and cisplatin

[0167] Agents affecting microtubule dynamics (e.g., vinblastine,vincristine, colchicine, paclitaxel and epothilone)

[0168] Caspase activators

[0169] Proteasome inhibitors

[0170] Angiogenesis inhibitors (e.g., endostatin, angiostatin andsqualamine)

[0171] Rapamycin, cerivastatin, flavopiridol and suramin

[0172] Matrix deposition/organization pathway inhibitors such ashalofuginone or other quinazolinone derivatives and tranilast

[0173] Endothelialization facilitators such as VEGF and RGD peptide

[0174] Blood rheology modulators such as pentoxifylline.

[0175] In addition, combinations of the above therapeutic agents can beused.

[0176] A wide range of therapeutic agent loadings can be used inconnection with the above block copolymers, with the amount of loadingbeing readily determined by those of ordinary skill in the art andultimately depending upon the condition to be treated, the nature of thetherapeutic agent itself, the means by which thetherapeutic-agent-loaded copolymer is administered to the intendedsubject, and so forth. The loaded copolymer will frequently comprisefrom less than one to 70 wt % therapeutic agent.

[0177] In many preferred embodiments of the invention, the copolymer isused to provide (a) the entirety of a medical device or (b) a portion ofa medical device (i.e., the copolymer is used as a “device or deviceportion”). Portions of medical devices for which the copolymers of thepresent invention find use include any fraction of a medical device,such as device coatings, device components and so forth.

[0178] In some instances, therapeutic agent is released from the deviceor device portion to a bodily tissue or bodily fluid upon contacting thesame. An extended period of release (i.e., 50% release or less over aperiod of 24 hours) may be preferred in some cases.

[0179] In other instances, for example, in the case where enzymes, cellsand other agents capable of acting on a substrate are used as atherapeutic agent, the therapeutic agent may remain within a copolymermatrix.

[0180] Preferred medical devices for use in conjunction with the presentinvention include catheters, preferably vascular catheters and morepreferably balloon catheters, guide wires, balloons, filters (e.g., venacava filters), vascular stents (including covered stents such as PTFE(polytetrafluoroethylene)-covered stents), stent grafts, cerebralstents, cerebral aneurysm filler coils (including GDC (Guglilmidetachable coils) and metal coils),vascular grafts, myocardial plugs,pacemaker leads, heart valves and intraluminal paving systems. Examplesof stents include NIR stents, Medinol, Israel, RADIUS stents, ScimedLife Systems, Maple Grove, Minn., WALLSTENT stents, Boston Scientific,Natick, Mass. and SYMPHONY stents, Boston Scientific Corp., Natick,Mass. The copolymers of the present invention can also be used incomposites for aneurysm fillers (e.g. polymeric mixtures of copolymerwith alginates, cyanoacrylates, hydrophilic polymers and so forth). Thecopolymers of the present invention are further useful to incorporatecells for cell therapy and are useful for tissue engineeringapplications (e.g., as scaffolds for cell delivery in cardiacapplications, liver regeneration, and so forth).

[0181] As noted above, the copolymer can comprise the entire device or aportion of the device, including a coating on the device or a componentof a device, and so forth.

[0182] Medical devices comprising a therapeutic-agent-loaded copolymerdevice or device portion in accordance with the present invention can beplaced in a wide variety of bodily locations for contact with bodilytissue or fluid. Some preferred placement locations include the coronaryvasculature or peripheral vascular system (referred to collectivelyherein as the vasculature), esophagus, trachea, colon, biliary tract,urinary tract, prostate and brain.

[0183] In some instances, it may be desirable to temporarily enclose thetherapeutic-agent-loaded copolymer to prevent release before the medicaldevice reaches its ultimate placement site. As a specific example, astent or catheter comprising therapeutic-agent-loaded copolymer can becovered with a sheath during insertion into the body to preventpremature therapeutic agent release.

[0184] Numerous techniques are available for creating medical devicesand device portions from the block copolymers described herein.

[0185] For example, the fact that the block copolymers havethermoplastic character opens up a variety of standard thermoplasticprocessing techniques for device and device portion formation, includingcompression molding, injection molding, blow molding, spinning, vacuumforming and calendaring, as well as extrusion into sheets, fibers, rods,tubes and other cross-sectional profiles of various lengths. Using theseand other techniques, devices such as balloons, catheters, stents andportions of devices can be made from the block copolymers.

[0186] Assuming that the therapeutic agent to be loaded is stable atprocessing temperatures, then it can be combined with the copolymer byextrusion prior to thermoplastic processing, producing atherapeutic-agent-loaded device or device portion. Otherwise, thetherapeutic agent can be loaded after formation of the device or deviceportion as discussed below.

[0187] Devices or device portions can also be made using solvent-basedtechniques in which the block copolymer is first dissolved in a solventand the block-copolymer solution is subsequently used to form the deviceor device portion. The solvent should, of course, be compatible with theblock copolymer. As an example, compatible solvents for block copolymersof styrene and isobutylene include tetrahydrofuran, toluene, xylene,hexanes, heptanes, combinations of the above and the like. Preferredtechniques of this nature include solvent casting, spin coating, webcoating, solvent spraying, dipping, fiber forming, ink jet techniquesand the like. In many cases, the solution is applied to a template, andthe desired component is obtained, after solvent elimination, by simplyremoving the block copolymer from the template. Such techniques areparticularly appropriate for forming simple objects such as sheets,tubes, cylinders and so forth.

[0188] One example of a solvent-based technique for forming a device ordevice portion can be found, in Example 3 of U.S. Pat. No. 5,741,331 toPinchuk. In this example, styrene/isobutylene copolymer is dissolved inthe amount of 6% solids (unless indicated otherwise, all percentagesherein are weight percentages) in tetrahydrofuran and the resultingsolution sprayed with an airbrush onto a rotating mandrel, which acts asa template. The environment is controlled during spraying so that thetetrahydrofuran evaporates between the sprayer and the mandrel, allowinga porous mat to be formed on the rotating mandrel. These samples arethen fully dried in air and removed from the mandrel. Such a techniquecan be used to form, for example, vascular grafts, stent-grafts,vascular patches, hernia patches, heart valve sewing rings, and thelike.

[0189] When forming devices or device portions containing a therapeuticagent using solvent-based techniques, so long as the solvent iscompatible with the therapeutic agent, the therapeutic agent can beprovided in the copolymer/solvent mixture, for example, in dissolvedform or as a particulate suspension. Such techniques allow thetherapeutic agent to be loaded concurrently with component formation.

[0190] If desired, the copolymer/solvent mixture can contain more thanone solvent (for example, one solvent appropriate for the blockcopolymer and a different solvent appropriate for the therapeuticagent). As a specific non-limiting example, where paclitaxel is selectedas a drug and where the copolymer is the triblockpolystyrene-polyisobutylene-polystyrene, a solution made from toluene,tetrahydrofuran, paclitaxel and the copolymer can be used.

[0191] In cases where the therapeutic agent is not provided at the sametime as device or device portion formation, if desired, the therapeuticagent can be loaded subsequent to component formation as discussedfurther below.

[0192] A coating is a preferred device portion that is frequently usedin connection with the present invention. For example, the copolymersdisclosed herein can be used to form coatings on medical device surfaces(e.g., internal or external surfaces). Such surfaces are formed from awide variety of materials, including glass, metals, polymers, ceramicsand combinations thereof.

[0193] Various techniques are available for forming coatings of thecopolymer on surfaces of medical devices.

[0194] For example, coatings can be formed via thermoplastic processing,for example, by co-extruding the coating along with a medical devicecomponent.

[0195] In a preferred technique, the copolymer is first dissolved in asolvent that is compatible with the copolymer, followed by applicationof the copolymer solution to at least a portion of a medical device.Preferred techniques include solvent casting, spin coating, web coating,solvent spraying, dipping, ink jet and combinations of these processes.If desired (for example, to achieve a desired coating thickness), suchcoating techniques can be repeated or combined to build up the coatedlayer to the desired thickness. Coating thickness can be varied in otherways as well. For example, in one preferred process, solvent spraying,coating thickness can be increased by modification of the coatingprocess parameters such as increasing flow rate, slowing the movementbetween the device to be coated and the spray nozzle, providing repeatedpasses, and so forth. In general the ultimate coating ranges from about0.5 micron to 50 microns in thickness, more preferably 2 to 30 microns.

[0196] If desired, a therapeutic agent of interest can be provided atthe same time as the copolymer coating, for example, by adding it to acopolymer melt during thermoplastic processing or by adding it to acopolymer solution during solvent-based processing as discussed above.Alternatively, it can be added after the coating is formed as discussedfurther below.

[0197] As previously noted, in some embodiments of the presentinvention, a therapeutic agent is provided after formation of the deviceor device portion. As an example of these embodiments, the therapeuticagent can be dissolved in a solvent that is compatible with both thecopolymer and the therapeutic agent. Preferably, the coating orcomponent is at most only slightly soluble in the solvent. Subsequently,the solution is contacted with the device or device portion such thatthe therapeutic agent is loaded (e.g., by leaching/diffusion) into thecopolymer. For this purpose, the device or device portion can beimmersed or dipped into the solution, the solution can be applied to thedevice or component, for example, by spraying, and so forth. The deviceor component can subsequently be dried, with the therapeutic agentremaining therein.

[0198] In several examples given above, the therapeutic agent isprovided within a matrix comprising the copolymer of the presentinvention. The therapeutic agent can also be covalently bonded, hydrogenbonded, or electrostatically bound to the copolymer. As specificexamples, nitric oxide releasing functional groups such asS-nitroso-thiols can be provided in connection with the copolymer, orthe copolymer can be provided with charged functional groups to attachtherapeutic groups with oppositely charged functionalities.

[0199] Alternatively, the therapeutic agent can be precipitated onto thesurface of a device or device portion. This surface can be subsequentlycovered with a coating of copolymer (with or without additionaltherapeutic agent) as described above.

[0200] Hence, when it is stated herein that the block copolymer is“loaded” with therapeutic agent, it is meant that the therapeutic agentis associated with the block copolymer in a fashion like those discussedabove or in a related fashion.

[0201] As previously noted, block copolymers of the present inventioncan be used to form entire medical devices or various portions of suchmedical devices. Examples include the use of the block copolymers of thepresent invention (1) as a single device, (2) as a combination ofdevices, (3) as a single device portion (such as a device component or adevice coating), (4) as a combination of device portions, and so forth.

[0202] The block copolymers can also be used in connection with furtherauxiliary materials or device portions to achieve a desired result. Suchauxiliary materials or device portions include binders, boundary layers,blending agents, and so forth.

[0203] For example, in some instances a binder may be useful foradhesion to a substrate. Examples of materials appropriate for bindersin connection with the present invention include silanes, titanates,isocyanates, carboxyls, amides, amines, acrylates hydroxyls, andepoxides, including specific polymers such as EVA, polyisobutylene,natural rubbers, polyurethanes, siloxane coupling agents, ethylene andpropylene oxides.

[0204] It also may be useful to coat the copolymer of the presentinvention (which may or may not contain a therapeutic agent) with alayer with an additional polymer layer (which may or may not contain atherapeutic agent). This layer may serve, for example, as a boundarylayer to retard diffusion of the therapeutic agent and prevent a burstphenomenon whereby much of the agent is released immediately uponexposure of the device or device portion to the implant site. Thematerial constituting the coating, or boundary layer, may or may not bethe same copolymer as the loaded copolymer.

[0205] For example, the barrier layer may also be a polymer or smallmolecule from the following classes: polycarboxylic acids, includingpolyacrylic acid; cellulosic polymers, including cellulose acetate andcellulose nitrate; gelatin; polyvinylpyrrolidone; cross-linkedpolyvinylpyrrolidone; polyanhydrides including maleic anhydridepolymers; polyamides; polyvinyl alcohols; copolymers of vinyl monomerssuch as EVA (ethylene-vinyl acetate copolymer); polyvinyl ethers;polyvinyl aromatics; polyethylene oxides; glycosaminoglycans;polysaccharides; polyesters including polyethylene terephthalate;polyacrylamides; polyethers; polyether sulfone; polycarbonate;polyalkylenes including polypropylene, polyethylene and high molecularweight polyethylene; halogenated polyalkylenes includingpolytetrafluoroethylene; polyurethanes; polyorthoesters; polypeptides,including proteins; silicones; siloxane polymers; polylactic acid;polyglycolic acid; polycaprolactone; polyhydroxybutyrate valerate andblends and copolymers thereof; coatings from polymer dispersions such aspolyurethane dispersions (BAYHDROL®, etc.); fibrin; collagen andderivatives thereof; polysaccharides such as celluloses, starches,dextrans, alginates and derivatives; and hyaluronic acid.

[0206] Copolymers and mixtures of the above are also contemplated.

[0207] A preferred polymer is polyacrylic acid, available as HYDROPLUS®(Boston Scientific Corporation, Natick, Mass.), and described in U.S.Pat. No. 5,091,205, the disclosure of which is hereby incorporatedherein by reference. In a most preferred embodiment of the invention,the polymer is a copolymer of polylactic acid and polycaprolactone.

[0208] It is also possible to form blends by adding one or more of theabove or other polymers to the block copolymers of the presentinvention. Examples include the following:

[0209] Blends can be formed with homopolymers that are miscible with oneof the block copolymer phases. For example, polyphenylene oxide ismiscible with the styrene blocks ofpolystyrene-polyisobutylene-polystyrene copolymer. This should increasethe strength of a molded part or coating made frompolystyrene-polyisobutylene-polystyrene copolymer and polyphenyleneoxide.

[0210] Blends can be made with added polymers or other copolymers thatare not completely miscible with either of the blocks of the blockcopolymers of the present invention. The added polymer or copolymer maybe advantageous, for example, in that it is compatible with anothertherapeutic agent, or it may alter the release rate of the theraputicagent from the block copolymers of the present invention (e.g.,polystyrene-polyisobutylene-polystyrene copolymer).

[0211] Blends can be made with a component such as sugar (see listabove) that can be leached from the device or device portion, renderingthe device or device component more porous and controlling the releaserate through the porous structure.

[0212] The therapeutic-agent-loaded block copolymers are appropriate fora number of administration avenues including insertion or implantationinto the body. Where the block copolymers are to be inserted orimplanted for an extended period of time, biocompatibility is ofconcern.

[0213] The release rate of therapeutic agent from thetherapeutic-agent-loaded block copolymers of the present invention canbe varied in a number of ways. Examples include:

[0214] varying the molecular weight of the block copolymers,

[0215] varying the specific constituents selected for the elastomericand thermoplastic portions of the block copolymers and the relativeamounts of these constituents,

[0216] varying the type and relative amounts of solvents used inprocessing the block copolymers,

[0217] varying the porosity of the block copolymers,

[0218] providing a boundary layer over the block copolymer, and

[0219] blending the block copolymers of the present invention with otherpolymers or copolymers.

[0220] As noted above, the block copolymers used in connection with thepresent invention are endowed with good biocompatibility. Thebiocompatibility of polystyrene-polyisobutylene-polystyrene copolymersaccording to an embodiment of the invention is demonstrated below inconnection with Example 6.

[0221] The invention is further described with reference to thefollowing non-limiting examples.

EXAMPLE 1 Block Copolymer Synthesis.

[0222] A styrene-isobutylene-styrene block copolymer is synthesizedusing known techniques. As is well known by those versed in the art ofcationic chemistry, all solvents and reactants must be moisture, acidand inhibitor-free. Therefore, it may be necessary, depending upon thegrade of material purchased, to distill these chemicals or flow themthrough columns containing drying agents, inhibitor removers and thelike, prior to introducing them into the reaction procedure.

[0223] Assuming that all solvents are pure and moisture- andinhibitor-free, styrene is added to a dried, airtight styrene mixingtank. The tank is initially chilled to between −19° C. (the condensationpoint of methyl chloride) and −31° C. (the freezing point of purestyrene) using liquid nitrogen or other heat transfer media, whereuponmethyl chloride gas is condensed and added. Next, di tert-butyl-pyridineis mixed with hexanes and added to the styrene tank, followed byflushing with further hexanes. Isobutylene is then added to the styrenetank, followed by sufficient hexanes to bring total hexane weight in thestyrene mixing tank to the desired amount. The temperature is thenbrought to about −70° C. and maintained at that temperature until used.

[0224] Hexanes are discharged into a dried, airtight reactor, containingcooling coils and a cooling jacket. The reactor with the hexanes iscooled with liquid nitrogen or other heat transfer media. Methylchloride is condensed into the reactor by bubbling the gas through thecooled hexanes. A hindered t-butyl dicumyl ether, dimethyl phthalate anddi tert-butyl-pyridine are added to the reactor, flushing with hexanes.Isobutylene is charged and condensed into the reactor by bubbling thegas thought the cooled solvent system. The temperature is maintained atabout −70° C. After the isobutylene is added to the reactor, titaniumtetrachloride is then charged to the reactor, flushing with hexanes, tostart the reaction. After the appropriate amount of isobutylene has beenadded, the reaction is allowed to continue for 15 to 30 min. Thecontents of the styrene tank (prechilled to −60 to −70° C.) are thenadded to the reactor, maintaining the reactor at a temperature of about−70° C. After adding all the contents of the styrene tank, the contentsof the reactor are allowed to react an additional 15 to 45 minutes,whereupon the reaction is quenched with methanol.

[0225] The reactor is then allowed to warm to room temperature, whilebeing aware of any pressure increases, and the methyl chloride isremoved from the reactor by boiling it and condensing it into a chilledcollection tank. An additional amount of hexanes, or other solvent, suchas tetrahydrofuran or toluene is added to the reactor to replace theremoved methyl chloride. These additional solvents are used tosolubilize the polymer to enable it to be drained out of the reactor, asotherwise the polymer becomes too thick to readily flow. The copolymersolution from the reactor is then precipitated in methanol (equal inweight to the initial copolymer/hexanes to be coagulated). Theprecipitated polymer is then poured into a sieve, the polymer removedand dried in a vacuum oven for at least 24 hours at approximately 125°C. under full vacuum.

EXAMPLE 2 Solvent-Based Coating Technique

[0226] An example of a solvent-based technique for coating a medicaldevice, such as a stent, follows. As always, the solvent system selectedfor use in such a procedure will depend upon the nature of the blockcopolymer and therapeutic agent selected. In the case of apolystyrene-polyisobutylene-polystyrene triblock copolymer andpaclitaxel therapeutic agent, a preferred solution is one containing (1)between 0-94%, preferably 94%, toluene, (2) between 5%-99%, preferably5%, tetrahydrofuran and (3) 1% copolymer and paclitaxel combined. Such asolution can be provided by (1) mixing the paclitaxel andtetrahydrofuran, (2) adding the copolymer, (3) adding the toluene, (4)thorough mixing (e.g., overnight), and (5) filtering (e.g., through afine filter such as a 0.22 micron filter). The solution of interest canthen be placed in a syringe pump, and the fluid can be fed to a spraynozzle. The component of interest (e.g., catheter, catheter balloon,stent, stent graft, vascular graft, etc.) can be mounted onto a holdingdevice parallel to the nozzle and, if desired, rotated (e.g., at 45 RPM)to ensure uniform coverage. Depending on the spray equipment used,either the component or spray nozzle can be moved while spraying suchthat the nozzle moves along the component while spraying for one or morepasses. For instance, a nozzle pressurized at 15 psi for a flow rate of6.3 mL/hr solution (polystyrene-polyisobutylene-polystyrene copolymer,paclitaxel, toluene and tetrahydrofuran), provided at a distance of 1.0inch from the component and moved relative to the component between0.3-0.5 mm/sec can produce a thickness of 2.5 to 4.0 microns.

EXAMPLE 3 Solvent-Based Coating Technique

[0227] In another preferred process, a solution like that abovecontaining (1) between 0-94% toluene, (2) between 5-99% tetrahydrofuranand (3) 1% polystyrene-polyisobutylene-polystyrene copolymer andpaclitaxel is sprayed with an airbrush onto a rotating medical devicecomponent, such as a stent. The environment is controlled duringspraying so that the tetrahydrofuran and toluene evaporates between thesprayer and the component, allowing a porous mat loaded with atherapeutic agent to be formed on the rotating component. Spraying isstopped when the desired coating thickness is achieved.

EXAMPLE 4 Drying Process

[0228] After a component or layer has been formed using one of the abovesolvent-based techniques, the component or layer can be dried, forexample, by placing it in a preheated oven (e.g., for 30 minutes at 65°C., followed by 3 hours at 70° C.).

EXAMPLE 5 Release Characteristics

[0229] The release rate can be varied by varying the relative amounts ofdrug and copolymer. FIG. 1 illustrates release rate as a function oftime for NIR stents coated with polystyrene-polyisobutylene-polystyrenecopolymer and paclitaxel in varying ratios. The coating formulationswere made with 94% toluene and 5% tetrahydrofuran, with the remaining 1%of the formulation being made up of paclitaxel and styrene-isobutylenecopolymer in respective relative amounts of 35%-65%, 32.5%-67.5%,30%-70%, 25%-75%, 22.5%-87.5%, 20%-80% and 17.5%-83.5% with anequivalent total coating weight. Coating thickness was about 16 microns.The release rates in FIG. 1 range from a relatively rapid release inconnection with the highest paclitaxel value (35%) to a relatively slowrelease at the lowest value (17.5%).

EXAMPLE 6 Biocompatibility

[0230] For this investigation, the following are provided: (1) a barestainless steel NIR (Medinol, Israel) stent; (2) a NIR stent with acoating of traditional “biostable” polycarbonate urethane polymer(Chronoflex AL, CardioTech Inc., Woburn Mass.); (3) a NIR stent with acoating of a traditional “biodegradable” copolymer of polylactic acid(“PLA”) and polyglycolic acid (“PGA”) (Birmingham Polymers, Birmingham,Ala.); and (4) a NIR stent with a coating ofpolystyrene-polyisobutylene-polystyrene copolymer in accordance with thepresent invention.

[0231] These stents were implanted in a porcine coronary artery. After28 days, the stent was harvested from the animal and examined for bothstenosis (neointimal thickening) and inflammation. Stenosis was measuredangiographically. Inflammation was measured by blinded observers basedon microscopic inspection of sections retrieved from the porcine artery.Inflammation values of 1 to 4 were assigned, with 1 representing theminimal inflammation and 4 representing maximal inflammation. Theresults are presented in the following table: Coating Stenosis (%)Inflammation None (Bare Stent) 43 ± 7 2.6 ± 0.7 Polycarbonate urethane75 ± 15 3.9 ± 0.8 Polystyrene-polyisobutylene- 47 ± 9 1.5 ± 0.5polystyrene copolymer PLA/PGA copolymer — —

[0232] As can be seen from this table, stenosis and inflammation weresignificantly higher with the stents coated with traditionalpolycarbonate urethane polymer than was observed than with the barestent or with the stents coated withpolystyrene-polyisobutylene-polystyrene copolymer.

[0233]FIGS. 2A, 2B, 2C and 2D show representative histology of thesections from the stented arteries. The extent of inflammation andneointimal thickness was much more pronounced in FIG. 2C (appearance ofthe vessel associated with the traditional “biostable”polyurethane-carbonate-coated stent) and FIG. 2D (traditional“biodegradable” PLA/PGA copolymer), than in FIG. 2A (bare stent) or FIG.2B (polystyrene-polyisobutylene-polystyrene coated stent).

[0234] Although various embodiments are specifically illustrated anddescribed herein, it will be appreciated that modifications andvariations of the present invention are covered by the above teachingsand are within the purview of the appended claims without departing fromthe spirit and intended scope of the invention.

What is claimed is:
 1. A composition for delivery of a therapeutic agentcomprising: a biocompatible block copolymer comprising one or moreelastomeric blocks and one or more thermoplastic blocks; and atherapeutic agent, said block copolymer being loaded with saidtherapeutic agent.
 2. The composition of claim 1, wherein said one ormore elastomeric blocks are polyolefin blocks and wherein said one ormore thermoplastic blocks are selected from vinyl aromatic blocks andmethacrylate blocks.
 3. The composition of claim 1, wherein said blockcopolymer is of the formula X-(AB)_(n), where A is an elastomeric block,B is a thermoplastic block, n is a positive whole number and X is a seedmolecule
 4. The composition of claim 3, wherein A is a polyolefin blockand B is a vinyl aromatic block or a methacrylate polymer block.
 5. Thecomposition of claim 4, wherein B comprises one or more monomersselected from methylmethacrylate, ethylmethacrylate and hydroxyethylmethacrylate.
 6. The composition of claim 4, wherein A is a polyolefinblock of the general formula —(CRR′—CH₂)_(n)—, where R and R′ are linearor branched aliphatic groups or cyclic aliphatic groups and wherein B isa vinyl aromatic polymer block.
 7. The composition of claim 6, whereinsaid polyolefin block comprises an isobutylene monomer and wherein saidvinyl aromatic polymer block comprises one or more monomers selectedfrom styrene and a-methylstyrene.
 8. The composition of claim 6, whereinthe amount of polyolefin blocks ranges from between 95 and 45 mol % ofthe block copolymer.
 9. The composition of claim 6, wherein themolecular weight of the block copolymer ranges from 80,000 to 300,000Daltons.
 10. The composition of claim 6, wherein the molecular weight ofthe polyolefin blocks ranges from 60,000 to 200,000 and the molecularweight of the vinyl aromatic polymer blocks ranges from 20,000 to100,000.
 11. The composition of claim 2, wherein said loaded blockcopolymer comprises 0.1 to 70 wt % therapeutic agent.
 12. Thecomposition of claim 6, wherein said loaded block copolymer comprises0.1 to 70 wt % therapeutic agent.
 13. The composition of claim 7,wherein said loaded block copolymer comprises 0.1 to 70 wt % therapeuticagent.
 14. A medical device, at least a portion of which is insertableor implantable into the body of a patient, comprising: a block copolymercomprising one or more elastomeric blocks and one or more thermoplasticblocks; and a therapeutic agent, said block copolymer being loaded withsaid therapeutic agent.
 15. The medical device of claim 14, wherein saidone or more elastomeric blocks are polyolefin blocks and wherein saidone or more thermoplastic blocks are vinyl aromatic b lock s ormethacrylate blocks.
 16. The medical device of claim 14, wherein saidblock copolymer is of the formula X-(AB)_(n), where A is an elastomericblock, B is a thermoplastic block, n is a positive whole number and X isa seed molecule.
 17. The medical device of claim 16, wherein A is apolyolefin block and B is a vinyl aromatic block or methacrylate polymerblock.
 18. The medical device of claim 17, wherein A is a polyolefinblock of the general formula —(CRR′—CH₂)_(n)—, where R and R′ are linearor branched aliphatic groups or cyclic aliphatic groups and wherein B isa vinyl aromatic polymer block.
 19. The medical device of claim 18,wherein said polyolefin block comprises an isobutylene monomer andwherein said vinyl aromatic polymer block comprises one or more monomersselected from polystyrene and poly-α-methylstyrene.
 20. The medicaldevice of claim 15, wherein only a portion of said medical devicecomprises said block copolymer.
 21. The medical device of claim 20,wherein said portion of said medical device is a coating on said medicaldevice.
 22. The medical device of claim 15, wherein therapeutic agent isreleased over an extended period after implantation in a patient
 23. Themedical device of claim 15, wherein the medical device is adapted suchthat at least a portion of said block copolymer is exposed to bodilyfluid upon insertion or implantation in the body
 24. The medical deviceof claim 15, wherein the medical device is adapted such that at least aportion of said block copolymer is exposed to tissue upon insertion orimplantation in the body.
 25. The medical device of claim 15, whereinsaid medical device is a catheter, guide wire, balloon, filter, stent,stent graft, vascular graft, vascular patch, shunt or intraluminalpaving system.
 26. The medical device of claim 15, wherein said medicaldevice is adapted for implantation or insertion into the coronaryvasculature, peripheral vascular system, esophagus, trachea, colon,biliary tract, urinary tract, prostate or brain.
 27. The medical deviceof claim 15, wherein said medical device is a stent or catheter whichfurther comprises a sheath for covering the block copolymer duringinsertion into the body to prevent premature therapeutic agent release.28. The medical device of claim 21, wherein said coating ranges fromabout 0.1 to 50 microns in thickness.
 29. The medical device of claim15, wherein said therapeutic agent is selected from one or more of thegroup consisting of an anti-thrombotic agent, an anti-proliferativeagent, an anti-inflammatory agent, an anti-migratory agent, an agentaffecting extracellular matrix production and organization, anantineoplastic agent, an anti-mitotic agent, an anesthetic agent, ananti-coagulant, a vascular cell growth promotor, a vascular cell growthinhibitor, a cholesterol-lowering agent, a vasodilating agent, and anagent that interferes with endogenous vascoactive mechanisms.
 30. Themedical device of claim 15, wherein said therapeutic agent is selectedfrom anti-sense DNA, anti-sense RNA, DNA coding for anti-sense RNA, DNAcoding for tRNA or rRNA, DNA coding for angiogenic factors, DNA codingfor cell cycle inhibitors, DNA coding for cell proliferation inhibitionagents, and DNA coding for bone morphogenic proteins.
 31. The medicaldevice of claim 15, wherein said therapeutic agent is selected fromautologous cells, allogeneic cells and xenogeneic cells.
 32. A method oftreatment comprising implanting or inserting the device of claim 15 intoa patient such that said therapeutic agent is released in said patientover an extended period.
 33. A medical device, at least a portion ofwhich is insertable or implantable into the vasculature of a patient,comprising: a block copolymer portion of the formula X-(AB)_(n), whereinA is a polyolefin block of the general formula —(CRR′—CH₂)_(n)—, where Rand R′ are linear or branched aliphatic groups or cyclic aliphaticgroups, B is a vinyl aromatic polymer block, n is a positive wholenumber and X is a seed molecule; and a therapeutic agent, said blockcopolymer being loaded with said therapeutic agent, and said therapeuticagent selected from of one or more of the group consisting of ananti-thrombotic agent, an anti-proliferative agent, an anti-inflammatoryagent, an anti-migratory agent, an agent affecting extracellular matrixproduction and organization, an antineoplastic agent, an anti-mitoticagent, an anesthetic agent, an anti-coagulant, a vascular cell growthpromotor, a vascular cell growth inhibitor, a cholesterol-loweringagent, a vasodilating agent, and an agent that interferes withendogenous vascoactive mechanisms.
 34. The medical device of claim 33,wherein said polyolefin block is a polyisobutylene block and whereinsaid vinyl aromatic polymer block comprising one or more monomersselected from polystyrene and poly-α-methylstyrene.
 35. The medicaldevice of claim 33, wherein said medical device is selected from acatheter, guide wire, balloon, filter, stent, stent graft, vasculargraft, vascular patch or intraluminal paving system.
 36. The medicaldevice of claim 33, wherein said block copolymer is in the form of acoating over at least a portion of said medical device.
 37. The medicaldevice of claim 34, wherein said block copolymer is in the form of acoating over at least a portion of a medical device selected from thegroup consisting of a balloon, a stent and a shunt, a catheter, and afilter wherein said therapeutic agent is paclitaxel.
 38. The medicaldevice of claim 37, wherein said coating ranges from 0.1 to 40 micronsin thickness.
 39. The medical device of claim 37, wherein said loadedblock copolymer portion comprises 0.1 to 75 wt % paclitaxel.
 40. Themedical device of claim 37, wherein the molecular weight of thepolyisobutylene blocks ranges from 60,000 to 200,000 and the molecularweight of the polystyrene or poly-α-methylstyrene blocks ranges from20,000 to 100,000.
 41. A coated medical device comprising: anintravascular or intervascular medical device; and a coating over atleast a portion of said intravascular or intervascular medical device,said coating comprising a biocompatible block copolymer comprising oneor more elastomeric blocks and one or more thermoplastic blocks.
 42. Thecoated medical device of claim 41, wherein said one or more elastomericblocks are polyolefin blocks and wherein said one or more thermoplasticblocks are selected from vinyl aromatic blocks and methacrylate blocks.43. The coated medical device of claim 41, wherein said block copolymeris of the formula X-(AB)_(n), where A is an elastomeric block, B is athermoplastic block, n is a positive whole number and X is a catalystseed molecule.
 44. The coated medical device of claim 43, wherein A is apolyolefin block and B is a vinyl aromatic block or a methacrylatepolymer block.
 45. The coated medical device of claim 44, wherein Bcomprises one or more monomers selected from methylmethacrylate,ethylmethacrylate and hydroxyethyl methacrylate.
 46. The coated medicaldevice of claim 44, wherein A is a polyolefin block of the generalformula —(CRR′—CH₂)_(n)—, where R and R′ are linear or branchedaliphatic groups or cyclic aliphatic groups and wherein B is a vinylaromatic polymer block.
 47. The coated medical device of claim 46,wherein said polyolefin block comprises an isobutylene monomer andwherein said vinyl aromatic polymer block comprises one or more monomersselected from styrene and α-methylstyrene.
 48. The coated medical deviceof claim 46, wherein the amount of polyolefin blocks ranges from between95 and 45 mol % of the block copolymer.
 49. The coated medical device ofclaim 46, wherein the molecular weight of the block copolymer rangesfrom 80,000 to 300,000 Daltons.
 50. The coated medical device of claim46, wherein the molecular weight of the polyolefin blocks ranges from60,000 to 200,000 Daltons and the molecular weight of the vinyl aromaticpolymer blocks ranges from 20,000 to 100,000 Daltons.
 51. The device ofclaim 40, wherein said intravascular or intervascular medical device isselected from a balloon, a stent, a shunt, a catheter, a stent graft, avascular graft, a vascular patch, a shunt and a filter.
 52. The medicaldevice of claim 14, further comprising a polymer or copolymer of one ormore of the following: a polycarboxylic acid, a cellulose acetatepolymer, a cellulose nitrate polymer, a gelatin, a polyvinylpyrrolidone,a cross-linked polyvinylpyrrolidone, a polyanhydride, a polyamide, apolyvinyl alcohol, a polyvinyl ether, a polyvinyl aromatic, apolyethylene oxide, a glycosaminoglycan, a polysaccharide, a polyester,a polyacrylamide, a polyether, a polyether sulfone, a polycarbonate, apolyalkylene, a halogenated polyalkylene, a polyurethane, apolyorthoester, a polypeptide, a silicone, a siloxane polymer, apolylactic acid, a polyglycolic acid, a polycaprolactone, apolyhydroxybutyrate valerate, a fibrin, a collagen, a collagenderivative or a hyaluronic acid.
 53. The medical device of claim 52,wherein said polymer or copolymer is selected from a polyacrylic acid,an ethylene-vinyl acetate copolymer, and a copolymer of polylactic acidand polycaprolactone.
 54. The medical device of claim 52, wherein saidpolymer or copolymer is blended with said biocompatible block copolymer.55. The medical device of claim 52, wherein said polymer or copolymer isprovided in a layer that does not contain said biocompatible blockcopolymer.